Shigehiro Ohdo (1), Hirokazu Watanabe (2), Nobuya Ogawa (2), Yuji Yoshiyama (3) and Takashi Sugiyama (3)
(1) Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Graduate School, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812, Japan (2) Department of Pharmacology, Ehime University School of Medicine, Shigenobu-cho, Onsen-gun, Ehime 791-02, Japan (3) School of Pharmaceutical Sciences, Kitasato University, 9-1, Shirokane 5 Chome, Minato-ku, Tokyo 108, Japan
Abstract: The influence of dosing time on the embryotoxicity of sodium valproate (valproic acid, VPA) was investigated in ICR mice under a light-dark (12 : 12) cycle. A significant circadian rhythm was shown for VPA-induced embryotoxicity, with the highest value at 1700 and the lowest at 0100. A similar pattern of rhythm was also shown for VPA-induced toxicity in pregnant and nonpregnant mice. No significant dosing time-dependent difference between injection at 1700 and 0100 was demonstrated for VPA concentrations in the embryo, plasma and brain. The rhythm in the embryotoxicity seems to be related to the rhythm in the sensitivity of the embryo and dam to the drug. Embryotoxicity and VPA concentrations were significantly higher on gestational day 13 than day 7. The pharmacokinetics of VPA contribute, at least partly, to the gestational stage-dependent embryotoxicity of VPA. The timing of drug administration (i.e., gestational stage and circadian phase) appears to be essential for studies on the embryotoxicity of VPA in mice.
Sodium valproate, Embryotoxicity, Chronotoxicity
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